The terms phenolic and phenolic compound in the context of the present invention are defined chemically as a substance which has one or more aromatic rings and bears one or more hydroxyl substituents on the ring, including functional derivatives such as esters, methyl ethers, glycosides and other derivatives that are apparent to those skilled in the art. Phenol (hydroxybenzene) is the simplest example of a phenolic compound, but most phenolic compounds have two or more hydroxyl groups and are bioactive substances occurring widely in food plants that are eaten regularly by substantial numbers of animals and people and have been found to be safe compounds. Included in the definition of phenolics are polyphenols having complex substitution patterns, compounds having condensed rings, and phenolics containing one or more amine moieties and/or carboxylic acid moieties.
An example of a phenolic compound containing an amine moiety is p-aminophenol, the intermediate for paracetamol. An example of a phenolic compound containing both an amine and a carboxylic acid group is p-amino salicylic acid.
Phenolic and polyphenolic compounds are found widely in nature: in cereals, legumes, nuts, oilseeds, plant oils, fruits, vegetables, tea, coffee, cocoa, beer, wine, herbal products, such as Echinacea, ginseng, gingko biloba, St. John's wort, valerian, hawthorne, ginger, licorice, milk thistle, goldenseal, devil's claw, black cohosh, saw palmetto, and kava kava, for example. These substances are essential for growth and reproduction of plants and serve as antifeedants and antipathogens, among other purposes. Phenolic compounds aid in the maintenance of food, fresh flavor, taste, color and prevention of oxidation deterioration. In particular, many phenolic compounds are attracting the attention of food and medical scientists because of their antioxidative, anti-inflammatory, antimutagenic, and anticarcinogenic properties and their capacity to modulate key cellular enzyme functions. Phenolic pigment plant products and function as antibiotics, natural pesticides, signal substances for the establishment of symbiosis with rhizobia, attractants for pollinators, protective agents against ultraviolet light, insulating materials to make cell walls impermeable to gas and water and as structural materials to give plants stability. The members of this class have many valuable uses in the fields of nutrition, nutriceuticals, pharmaceuticals, medicine, agricultural chemistry and in other fields of technology.
Examples of naturally occurring phenolic compounds include, but are not limited to: bergaptol, caffeic acid, capsaicin, coumarin, daidzein, 2,5-dihydroxybenzoic acid, ferulic acid, flavonoids, glycitein (isoflavone), 4-hydroxycinnamic acid, 4-hydroxycoumarin, isopimpinellin, resveratrol, synapic acid, vanillic acid, vanillin, and the derivatives of all of the above.
Vanillin is a single-ring phenolic compound derived from the breakdown of lignin, a complex phenolic polymer that gives seasoned wood its color, hardness and mass. Natural vanilla flavoring comes from vanillin plus several other aromatic compounds in the seed capsules of the vanilla orchid. It is used as a flavoring agent in foods, beverages, confectionery, and pharmaceuticals. It is also used in perfumery.
Coumarin is a double-ring phenolic compound that imparts the distinctive sweet smell to newly mown hay. Coumarin is also an anticoagulant that represses the synthesis of prothrombin, a plasma protein produced in the liver in the presence of vitamin K. Prothrombin is the precurser of the enzyme thrombin, which catalyzes the conversion of fibrinogen to fibrin in the clotting process. Threads of fibrin wind around blood platelets in the damaged area of a blood vessel and provide a framework of a blood clot. Coumarin is converted into the anticoagulant dicoumarin during the improper curing of sweet clover hay. Aminocoumarins, such as novobiocin, clorobiocin and coumermycin A1, serve, among other uses, as antibiotics. Furanocoumarins, found in citrus fruits, celery, parsley, and parsnips, include the useful compounds psoralen, bergapten, xanthotoxin, isopimpinellin and 4,5′,8-trimethylenepsoralen. Isopimpinellin has been shown to block DNA adduct formation and skin tumor initiation in mice.
Flavonoids, sometimes called bioflavonoids, are 3-ring phenolic compounds consisting of a double ring attached by a single bond to a third ring. Examples include flavonoids, flavanones, flavones, flavanols, anthocyanidins, proanthocyanidins, procyanidolic oligomers (PCO), catechins, biflavans, polyphenols, rutin, rutinosides, hydroxyethylrutosides (HER), hesperidin, quercetin, quercetrin, polyphenols, catechin, epicatechin, epicatechin gallate, epigallocatechin gallate, and leucoanthocyanins. In leaves they block far ultraviolet light (which is highly destructive to nucleic acids and proteins), while selectively admitting light of blue and red wavelengths that is crucial for photosynthesis. Flavonoids include the water-soluble pigments, such as anthocyanins, that are found in cell vacuoles. Water-soluble flavonoids are responsible for the color of many flowers and can range from red to blue. Flavonols are colorless or yellow flavonoids found in leaves and many flowers. Some nutritionists recommend flavonoids (bioflavonoids and isoflavones) in order to maintain healthy tissues and promote the proper balance of hormones and antioxidants in the body. They may be obtained as supplements and from a good diet of fruits, vegetables and soy protein. Flavonoids possess the following important properties: anti-inflammatory, by inhibiting histamines, prostaglandins, and enzymes involved in the inflammatory response; anti-allergic, by inhibiting histamine production; anticarcinogenic, due to its antioxidant activity. As an antioxidant the flavonoids are more powerful free radical scavengers than Vitamin C and E.
A high bioflavonoid intake, according to the literature, is related to a lower risk of heart attack. Bioflavonoids have been shown to improve the integrity of small veins and capillaries, thus decreasing their permeability and fragility. A therapeutic dose of bioflavonoids is helpful for conditions related to chronic venous insufficiency (CVI). Some examples are: thrombophlebitis, thrombosis, varicose veins, leg ulcers, spider veins, hemorrhoids, chronic nosebleeds, prolonged menstrual bleeding. Even eye problems like macular degeneration and diabetic retinopathy have been helped with bioflavonoids. Bioflavonoids inhibit the destruction of collagen and actually support repair by cross-linking collagen fibers and reinforcing the connective tissue matrix. This means that, along with the anti-inflammatory effects, bioflavonoids can be very helpful for tendonitis, arthritis, rheumatoid arthritis, joint injury, fibromyalgia, cellulite, and gout. Bioflavonoids do not interact with most drugs.
Isoflavones exert a broad spectrum of biological activities. Besides antioxidant and estrogenic activities, isoflavones protect against several chronic diseases. Results of epidemiological studies indicate that consumption of soybean isoflavones lowers the incidence of breast, prostate, urinary tract and colon cancers. They also provide protection against coronary heart diseases and osteoporosis. Some examples of important isoflavones are isoflavone, daidzein, prunetin, biochanin A, orobol, santal, pratensein, formononetin, genistein, glycitein, and the glucosides, β-glycosides and other derivatives of the aforementioned isoflavones. This list is not meant to be all-inclusive.
Resveratrol, discovered in the grape skins of the grapes used to produce red wines, has been shown to lower the risk for coronary heart disease by inhibiting the plaque build-up or clogging of arteries by increasing the level of high density lipoproteins (HDLs) in the blood. Beneficial HDLs carry cholesterol away from the arteries so that it doesn't form plaque deposits in the arterial walls. Resveratrol also reduces blood platelet aggregation or clotting (thrombosis) within the blood vessels. Resveratrol belongs to the class of plant chemicals called phytoalexin. Plants use them as a defense mechanism in response to attacks by fungi and insects. One interesting phytoalexin called psolaren, having a chemical structure similar to coumarin, has been used in the treatment of certain cancers, including T-cell lymphomas in AIDS patients.
Bioflavonoids, specifically proanthcyanidins, are found in grape seed extract. The proanthcyanidins appear to enhance the activity of vitamin C. Vitamin C protects the cells from the damaging oxidation of free radicals, thus preventing mutations and tumor formation. The bioflavonoids in grape seed extract may also reduce the painful inflammation of swollen joints and prevent the oxidation of cholesterol in arteries that leads to plaque in the arterial walls.
Capsaicin is the active component of cayenne pepper. The capsaicins are amides of vanillylamine and C8 and C13 branched fatty acids. Topical application of capsaicin stimulates and blocks small pain fibers by depleting them of the neurotransmitter substance P that mediates pain impulses. A cream made from 0.025%-0.075% capsaicin applied 4× daily may help peripheral neuropathic pain, post-herpetic neuralgia, trigeminal neuralgia, psoriasis and fibromyalgia. It is also useful for diabetic neuropathy, cluster headaches, earache, osteo- and rheumatoid arthritis. Capsaicin is a powerful pain reliever.
Sinapinic acid (sinapic acid) and its esterified forms are the predominant phenolic acid compounds found in rapeseed, contributing to its flavor and aroma. The sinapinic acid compounds have been shown to exhibit an anti-inflammatory action and have antimicrobial properties.
Hydrocinnamic acids are the tea polyphenols, examples of which are chlorogenic acid, caffeic acid and ferulic acid. They have been shown to block the nitrosation of amines by reducing nitrate to nitric acid or by forming C-nitroso compounds, thus blocking hepatotoxicity, lowering the risk of breast cancer metastasis—green tea egcg (epigallocatechin-3-gallate).
Naproxen, paracetanol, acetaminophen and acetylsalicylic acid are phenolics that belong to the class of drugs called non-steroidal anti-inflammatory drugs or NSAIDs. The NSAIDs provide relief by blocking the action of prostaglandins, which are hormone-like substances that contribute to pain, inflammation, fever and muscle cramps.
Synthetic and naturally-occurring phenolic moieties, some of which may contain amine groups, carboxylic acid groups, or aminoacids, are part of many drugs. Examples of these medicinals include acenocoumarol, acetarsol, actinoquinol, adrenalone, alibendol, aminosalicylic acids, amodiaquine, anethole, balsalazide, bamethan, benserazide, bentiromide, benzarone, benzquinamide, bevantolol, bifluranol, buclosamide, bupheniode, chlorobiocin, chlorotrianisene, chloroxylenol, cianidanol, cinepazide, cinitapride, cinepazide, cinmetacin, clebopride, clemastine, clioquinol, coumermycin A1, cyclovalone, cynarine, denopamine, dextroythyroxine, diacerein, dichlorophen, dienestrol, diethylstilbestrol, diflunisal, diiodohydroxyquinoline, dilazep, dilevalol, dimestrol, dimoxyline, diosmin, dithranol, dobutamine, donepezil, dopamine, dopexamine, doxazosin, entacapone, epanolol, epimestrol, epinephrine, estradiol valerate, estriol, estriol succinate, estrone, etamivan, etamsylate, ethaverine, ethoxzolamide, ethyl biscoumacetate, etilefrine, etiroxate, exalamide, exifone, fendosal, fenoldopam mesilate, fenoterol, fenoxedil, fenticlor, flopropione, floredil, fluorescein, folescutol, formoterol, gallopamil, gentistic acid, glaziovine, glibenclamide, glucametacin, guajacol, halquinol, hexachlorophene, hexestrol, hexobendine, hexoprenaline, hexylresorcinol, hydroxyethyl salicylate, hydroxystilbamidine isethionate, hymecromone, ifenprodil, indometacin, ipriflavone, isoetarine, isoprenaline, isoxsuprine, itopride hydrochloride, ketobemidone, khellin, labetalol, lactylphenetidin, levodopa, levomepromazine, levorphanol, levothyroxine, mebeverine, medrylamine, mefexamide, mepacrine, mesalazine, mestranol, metaraminol, methocarbamol, methoxamine, methoxsalen, methyldopa, midodrine, mitoxantrone, morclofone, nabumetone, naproxen, nitroxoline, norfenefrine, normolaxol, novobiocin, octopamine, omeprazole, orciprenaline, oxilofrine, oxitriptan, oxyfedrine, oxypertine, oxyphenbutazone, oxyphenisatin acetate, oxyquinoline, papaverine, paracetanol, parethoxycaine, phenacaine, phenacetin, phenazocine, phenolphthalein, phenprocoumon, phentolamine, phloedrine, picotamide, pimobendan, prenalterol, primaquine, progabide, propanidid, protokylol, proxymetacaine, raloxifene hydrochloride, repaglinide, reproterol, rimiterol, ritodrine, salacetamide, salazosulfapyridine, salbutamol, salicylamide, salicylic acid, salmeterol, salsalate, sildenafil, silibinin, sulmetozin, tamsulosin, terazosin, terbutaline, tetroxoprim, theodrenaline, tioclomarol, tioxolone, α-tocopherol (vitamin E), tofisopam, tolcapone, tolterodine, tranilast, tretoquinol, triclosan, trimazosin, trimetazidine, trimethobenzamide, trimethoprim, trimetozine, trimetrexate glucuronate, troxipide, verapamil, vesnarinone, vetrabutine, viloxazine, warfarin, xamoterol.
Additional bioactive phenolic compounds include acacetin, 4-acetamido-2-methyl-1-naphthol, acetaminophen, albuterol, allenolic acid, aloe emodin, aloin, β-amino-4-hydroxy-3,5-diiodohydrocinnamic acid, N-(5-amino-2-hydroxyphenyl)-benzeneacetamide, 4-amino-1-naphthol, 3-aminosalicylic acid, 4-aminosalicylic acid, anacardic acid, p-anol, anthragallol, anthralin, anthranol, anthrarobin, anthrarufin, apigenin, apiin, apocynin, aspidinol, aspirin, baptigenin, benzestrol, benzoresorcinol, bisphenol A, bisphenol B, butylated hydroxyanisole, butylated hydroxytoluene, capobenic acid, trans-1-(3′-carboxy-4′-hydroxyphenyl)-2-(2″,5″-dihydroxyphenyl)ethane, catechin, chlorogenic acid, m-chlorophenol, 5-chloro-8-quinolinol, chloroxyphenol, chloroquinaldol, chromonar, chrysin, cinametic acid, clorophene, coniferyl alcohol, p-coumaric acid, coumarin-3-carboxylic acids, coumarin-8-carboxylic acids, coumestrol, coumetarol, daphnetin, datiscetin, deoxyepinephrine, 3,5-diiodothyronine, 3,5-diiodotyrosine, dimethophrine, diosmetin, diresorcinol, disoprofol, dopa, dopamine, drosophilin a, efloxate, ellagic acid, embelin, Equol, eriodictyol, esculetin, esculin, ethylnorepinephrine, ethyl vanillin, eugenol, eupatorin, fenadiazole, ferulic acid, fisetin, 3-fluoro-4-hydroxyphenylacetic acid, fraxetin, fustin, galangin, gallacetophenone, gallic acid, gardenins, genistein, gentisyl alcohol, gepefrine, geranylhydroquinone, [6]-gingerol, gossypol, guaiacol, guaifenesin, harmalol, hematoxylin, hinderin, homoeriodictyol, homogentisic acid, homovanillic acid, hydroxyamphetamine, 2-hyroxy-5-(2,5-dihydroxybenzylamino)-2-hydroxybenzoic acid, 4-hydroxy-3-methoxymandelic acid, n-(p-hydroxyphenyl)glycine, hydroxyprocaine, 8-hydroxyquinoline, hypericin, irigenin, isoproterenol, isoquercitrin, isothebaine, kaempferol, liothyronine, luteolin, mangostin, 7-methoxycoumarin-3-carboxylic acid, 5,5′-methylenedisalicylic acid, n-methylepinephrine, metyrosine, morin, mycophenolic acid, myricetin, naringenin, nylidrin, orcinol, osalmid, osthole, oxantel, paroxypropione, pentachlorophenol, 3-pentadecylcatechol, p-pentyloxyphenol, phloretin, phloroglucinol, pinosylvine, plumbagin, pyrocatechol, pyrogallol, quercetagetin, quercetin, resacetophenone, rhamnetin, rhein, sakuranetin, salicyl alcohol, salicylanilide, 4-salicyloylmorpholine, salsalate, scopoletin, scutellarein, serotonin, (3,4,5-trihydroxyphenyl)methylenepropanedinitrile, thymol, thyropropic acid, thyroxine, tiratricol, tyrosine, vanillic acid, and vanillin.
Reactions of phenolics with bioabsorbable polymers have been reported in Shalaby U.S. Pat. No. 5,082,925 and Matsuda US 20020169275. Reactions of bioactive compounds with bioabsorbable polymers have been reported, for example in Uhrich U.S. Pat. No. 6,468,519, Uhrich U.S. Pat. No. 6,689,350, and Kohn US20030216307.
Various types of controlled release technologies, some of which may be suitable for use with phenolic compounds have been reported in the literature. Examples are Yasukawa (2004), Blatt U.S. Pat. No. 6,890,561, Ould-Ouali (2005), Frank (2005), Chen U.S. Pat. No. 6,869,615, Cordes US 20050152958, Wynn US 20050095300, Mehta US 20050074493, Ng U.S. Pat. No. 6,861,068, Wong U.S. Pat. No. 6,773,721, Whitborne US 20040117007, and Shefer US 20030232091.
An article by G. A. Estrine (1989) speaks to the catalytic reaction of epsilon-caprolactone with diols to form an intermediate complex.
Uses of bioabsorbable polymers in the biomedical field have been reported, for example, in the following patents: Shalaby U.S. Pat. No. 4,130,639, Bezwada U.S. Pat. No. 4,532,928, Langer U.S. Pat. No. 4,886,870, Shalaby U.S. Pat. No. 4,605,730, Bezwada U.S. Pat. No. 4,653,497, Shalaby U.S. Pat. No. 4,689,424, Vacanti U.S. Pat. No. 5,759,830, Jamiolkowski U.S. Pat. No. 5,895,150, Bezwada U.S. Pat. No. 5,951,997, and Yiewen US 20050112171.
While phenolic compounds have various known beneficial uses, they generally are insoluble or partially soluble in water or the human body and are difficult to hydrolyze. They are also very difficult to polymerize in the phenolic state. It is desirable to do so and to be able to control their rate of action, target release into specific organs, extend release over a prolonged period of time and/or to delay or sustain their efficacy. The claimed invention corrects these drawbacks.